Controlled delivery of beneficial agents, especially peptide- and protein-based drug therapies, can be achieved through the use of bioerodible polymeric implants. Traditionally, this technology has involved surgical implantation of a polymeric monolith containing a suspended beneficial agent. Examples of these monoliths are described in U.S. Pat. Nos. 6,110,503, 6,051,259, and 6,146,662. Certain complex shapes and/or formulations of these monoliths have been developed to provide specific rates of release of the beneficial agent over a period of time. A drawback to this implantation approach is the need to perform an incision in the patient in order to place the implant.
In order to eliminate the need for surgical implantation, implants have been developed which can be administered by the injection of a viscous composition. Compositions for injection must have a sufficient ability to flow so that the implant can pass through a syringe and needle. However, these formulations should not simply dissipate into the body but rather should form a discrete depot from which the drug is released. Typically, the composition transforms into a solid or a gel upon encountering the aqueous environment within an organism.
To accomplish this balance of physical properties, various formulations of bioerodible polymers, biocompatible solvents, beneficial agents, and other ingredients have been employed. Release of the beneficial agent from the polymeric matrix of the implant can then occur by: diffusion of the agent from the matrix; by degradation of the polymer and subsequent release of the agent into the surrounding environment; or by a combination of these two mechanisms.
One approach to the formulation of injectable compositions has been the use of solvents which are miscible or dispersible with water (hydrophilic solvents). For example, U.S. Pat. No. 6,143,314 describes injectable compositions containing poly(lactic acid-co-glycolic acid) (PLGA) and a hydrophilic solvent such as dimethyl sulfoxide (DMSO) or N-methyl pyrrolidone (NMP). U.S. Pat. Nos. 5,278,201 and 4,938,763 describe poly(lactic acid), poly(glycolic acid), and their copolymers combined with NMP and a beneficial agent to form injectable liquid compositions. Depots of these same polymers also can be formed by injecting a composition containing a prepolymer, which then forms the polymer during the implantation process. As described in U.S. Pat. Nos. 5,340,849 and 5,278,202, compositions of NMP, a beneficial agent, and polymer precursors can form a polymer gel upon injection into an aqueous environment due to polymerization of the polymer precursors in the presence of water.
The beneficial agent can be either dissolved or dispersed in these formulations. Water-soluble beneficial agents, including peptides and proteins, are typically dissolved by the solvents which are miscible in aqueous body fluids. The solvents used in these compositions tend to provide for the rapid influx of water into the implant. This promotes rapid solidification of the polymer at the implant surface and promotes diffusion of the beneficial agent from the implant, often resulting in an initial, rapid release of the beneficial agent. This “burst” often results in the release of a substantial portion of the beneficial agent within a very short time. For example, 25-75% of the beneficial agent can be released within 24 hours of administration. In some cases, the burst can be followed by a drastic reduction in the release of the beneficial agent before a gradual release begins. This pause in the release behavior is referred to as a “lag time.”
A burst effect and/or lag time can be unacceptable, particularly in circumstances where sustained delivery is desired. For example, it may be desirable to deliver the beneficial agent over a period of a week or a month or longer. To control release rates of these systems, it is often necessary to include additional ingredients which can moderate the release of the beneficial agent and/or control the porosity of the implant. For example, U.S. Pat. Nos. 5,599,552 and 5,487,897 describe complex compositions which use poly(D,L-lactic acid) to provide an implant that has a porous or liquid core surrounded by a layer, or “skin,” of polymer. This morphology is reported to provide for a more uniform release rate. Release of a beneficial agent can also be controlled by complexing the agent to make it less soluble in water, as described in U.S. Pat. No. 5,780,044; however, complexation can affect the activity, and thus the efficacy, of the beneficial agent.
An alternative approach to the formulation of controlled release compositions has been the use of solvents which are immiscible with water. For example, U.S. Pat. No. 6,130,200 describes gels of PLGA and a water-immiscible (hydrophobic) solvent in which peptide-based drugs are suspended as particles. When administered, the gels have sufficient dimensional stability to form a cohesive depot. The hydrophobic solvent in these systems inhibits the rapid uptake of water, resulting in the reduction or elimination of any burst release. One drawback to this system is the high viscosities exhibited by the gels. Large diameter needles (16-gauge to 20-gauge) must be employed to administer the composition by injection, and high pressures are necessary for administration. This can be especially disadvantageous in the treatment of chronic conditions, such as the administration of insulin to diabetic patients. Another drawback is the tendency of the particulate beneficial agent to settle out of the composition over time. This instability can necessitate special storage conditions, short storage times, and/or special handling conditions during administration. If the beneficial agent settles out once the implant is in the organism, the rate of release of the agent over time can become unpredictable.
There is thus a need for compositions for the gradual release of a beneficial agent which can be easily administered by injection. These compositions will ideally exhibit controlled release of the agent, without unintended periods of rapid release or zero release. Additionally, stability for long periods of time and under various storage conditions would be desirable.